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In vivo expansion of functionally integrated GABAergic interneurons by targeted increase in neural progenitors.

ABSTRACT: A central hypothesis for brain evolution is that it might occur via expansion of progenitor cells and subsequent lineage-dependent formation of neural circuits. Here, we report in vivo amplification and functional integration of lineage-specific circuitry in Drosophila Levels of the cell fate determinant Prospero were attenuated in specific brain lineages within a range that expanded not only progenitors but also neuronal progeny, without tumor formation. Resulting supernumerary neural stem cells underwent normal functional transitions, progressed through the temporal patterning cascade, and generated progeny with molecular signatures matching source lineages. Fully differentiated supernumerary gamma-amino butyric acid (GABA)-ergic interneurons formed functional connections in the central complex of the adult brain, as revealed by in vivo calcium imaging and open-field behavioral analysis. Our results show that quantitative control of a single transcription factor is sufficient to tune neuron numbers and clonal circuitry, and provide molecular insight into a likely mechanism of brain evolution.

SUBMITTER: Shaw RE

PROVIDER: S-EPMC6028031 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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In vivo expansion of functionally integrated GABAergic interneurons by targeted increase in neural progenitors.

Shaw Rachel E RE Kottler Benjamin B Ludlow Zoe N ZN Buhl Edgar E Kim Dongwook D Morais da Silva Sara S Miedzik Alina A Coum Antoine A Hodge James Jl JJ Hirth Frank F Sousa-Nunes Rita R

The EMBO journal 20180504 13

A central hypothesis for brain evolution is that it might occur via expansion of progenitor cells and subsequent lineage-dependent formation of neural circuits. Here, we report in vivo amplification and functional integration of lineage-specific circuitry in Drosophila Levels of the cell fate determinant Prospero were attenuated in specific brain lineages within a range that expanded not only progenitors but also neuronal progeny, without tumor formation. Resulting supernumerary ne ...[more]

PMID: 29728368

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Project description:Fast-spiking (FS) interneurons are important elements of neocortical circuitry that constitute the primary source of synaptic inhibition in adult cortex and impart temporal organization on ongoing cortical activity. The highly specialized intrinsic membrane and firing properties that allow cortical FS interneurons to perform these functions are attributable to equally specialized gene expression, which is ultimately coordinated by cell-type-specific transcriptional regulation. Although embryonic transcriptional events govern the initial steps of cell-type specification in most cortical interneurons, including FS cells, the electrophysiological properties that distinguish adult cortical cell types emerge relatively late in postnatal development, and the transcriptional events that drive this maturational process are not known. To address this, we used mouse whole-genome microarrays and whole-cell patch clamp to characterize the transcriptional and electrophysiological maturation of cortical FS interneurons between postnatal day 7 (P7) and P40. We found that the intrinsic and synaptic physiology of FS cells undergoes profound regulation over the first 4 postnatal weeks and that these changes are correlated with primarily monotonic but bidirectional transcriptional regulation of thousands of genes belonging to multiple functional classes. Using our microarray screen as a guide, we discovered that upregulation of two-pore K leak channels between P10 and P25 contributes to one of the major differences between the intrinsic membrane properties of immature and adult FS cells and found a number of other candidate genes that likely confer cell-type specificity on mature FS cells. Experiment Overall Design: We characterized the transcriptional maturation of genetically labeled FS interneurons in mouse S1 cortex using whole-genome microarrays.mRNA was harvested from manually sorted GFPexpressing neurons dissociated from acutely prepared brain slices at a range of developmental time points (P7, P10, P15, P25, and P40) and subsequently reverse transcribed, amplified, labeled, and hybridized to Affymetrix 430 2.0 whole-genome microarrays (three microarrays from three different animals per condition). We used the G42 transgenic mice described by Chattopadhyaya et al. (2004) for all experiments.

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In vivo expansion of functionally integrated GABAergic interneurons by targeted increase in neural progenitors.

Publications

<i>In vivo</i> expansion of functionally integrated GABAergic interneurons by targeted increase in neural progenitors.

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Dataset Information

In vivo expansion of functionally integrated GABAergic interneurons by targeted increase in neural progenitors.

Publications

&lt;i&gt;In vivo&lt;/i&gt; expansion of functionally integrated GABAergic interneurons by targeted increase in neural progenitors.

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OmicsDI is part of the ELIXIR infrastructure

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<i>In vivo</i> expansion of functionally integrated GABAergic interneurons by targeted increase in neural progenitors.